Liver & intrahepatic bile ducts
Other malignancies
Cholangiocarcinoma (intrahepatic / peripheral)
Editorial Board Member: Raul S. Gonzalez, M.D.
Editor-in-Chief: Debra L. Zynger, M.D.
Topic Completed: 1 September 2018
Minor changes: 25 September 2020
Copyright: 2002-2021, PathologyOutlines.com, Inc.
PubMed Search: Cholangiocarcinoma [title] liver "intrahepatic bile duct"
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Savari O. Cholangiocarcinoma (intrahepatic / peripheral). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livertumorcholangiocarcinoma.html. Accessed January 18th, 2021.
Definition / general
- Intrahepatic cholangiocarcinoma is an epithelial malignancy arising from the intrahepatic biliary tree
- Recently divided into small duct type and large duct type, which have morphologic and molecular (but not prognostic) differences (Am J Surg Pathol 2018;42:1334, Surg Pathol Clin 2018;11:403)
Essential features
- Unencapsulated, white-tan and firm intrahepatic mass
- Glandular malignancy with various degrees of atypia and differentiation, infiltrating a dense fibrous stroma
- Exclusion of metastatic adenocarcinoma by thorough review of the patient's clinical history and application of an appropriate immunohistochemistry panel
Terminology
- Also known as peripheral cholangiocarcinoma and intrahepatic bile duct carcinoma
ICD coding
Epidemiology
- Incidence in the Western world is approximately 1 - 2 per 100,000 (J Cancer Res Clin Oncol 2011;137:1071)
- Comprises 15% of primary liver malignancies worldwide
- Second most common malignancy arising from the liver
- Accounts for 3% of all cases of gastrointestinal cancer
- Comprises about 10% of all cholangiocarcinomas
- More common in East Asia, due to endemic liver fluke infection
- More common in older patients (over 75% of patients are older than 65 at initial diagnosis) (Gastroenterology 2009;136:1134)
- Slightly more common in males than females (Hepatology 2011;54:173)
Pathophysiology
- Chronic inflammation of the intrahepatic bile ducts is a known risk factor in cholangiocarcinogenesis
- Proinflammatory cytokines activate inducible nitric oxide synthase resulting in oxidative DNA damage, inhibition of DNA repair enzymes and expression of cyclooxygenase 2 (COX2)
- These pathways also downregulate hepatobiliary transporters and cause cholestasis (Semin Liver Dis 2010;30:186)
- Bile acids and oxysterols activate epidermal growth factor receptor (EGFR) and enhance COX2 expression (Gastroenterology 2002;122:985)
- COX2 dysregulates cholangiocarcinoma growth and promotes apoptosis resistance and positively regulates pro-oncogenic signaling pathways such as hepatocyte growth factor (HGF), IL6 and EGFR (Semin Liver Dis 2010;30:186)
- TP53 and SMAD4 mutations are more frequent in liver fluke associated cholangiocarcinoma
- BAP1 and IDH1 / 2 mutations are more frequent in non liver fluke associated cholangiocarcinoma (Medicine (Baltimore) 2016;95:e2491)
Etiology
- No risk factors identified in the majority of cases (Ann Surg 2008;248:84)
- Primary sclerosing cholangitis: 5 - 20% lifetime risk of developing cholangiocarcinoma (Am J Gastroenterol 2004;99:523)
- Hepatobiliary parasites: Opisthorchis viverrini, Clonorchis sinensis
- Cirrhosis: independent risk factor (Gastroenterology 2005;128:620)
- Hepatolithiasis: more common in Southeast Asia and associated with a 6 to 50 fold increased risk
- Caroli disease: a congenital disorder characterized by multifocal, segmental dilatation of large intrahepatic bile ducts
- Choledochal cysts (types I and IV)
- Multiple bile duct hamartomas (von Meyenburg complexes) (Arch Pathol Lab Med 2000;124:1704)
- Thorotrast: a colloidal suspension of thorium dioxide that was used as an intravascular contrast agent until the 1950s with a 300 fold increased risk (Jarnagin: Blumgart's Surgery of the Liver, Biliary Tract and Pancreas, Volume 1, 6th Edition, 2017)
- Hepatitis C (World J Surg Oncol 2015;13:161)
Diagrams / tables
Images hosted on other servers:
Morphologic classification
Clinical features
- Asymptomatic in early stages (19 - 40% incidentally identified) (J Am Coll Surg 2001;193:384)
- Nonspecific symptoms in late stages, such as abdominal pain, malaise, night sweats and cachexia
Laboratory
- ↑ serum alkaline phosphatase
- ↑ total bilirubin
- ↑ aspartate aminotransferase
- ↑ serum CEA
- ↑ serum CA19-9
- Normal to slightly ↑ serum AFP
Radiology description
- Usually single, large, homogeneous mass with irregular margins on CT scan
- Intratumoral calcification is common
Radiology images
Images hosted on other servers:
CT scan
Ultrasound
MRI
Prognostic factors
- Tumor stage, microvascular invasion and lymph node metastasis are the most important prognostic factors (Oncol Rep 2013;29:1259)
Case reports
- 38 year old pregnant woman with 1 week history of headache, nausea, vomiting and right upper abdominal pain (Case Reports Hepatol 2018;2018:6939747)
- 45 year old Thai man with 3 month history of right upper abdominal pain (Case Rep Surg 2018;2018:3862575)
- 58 year old woman with abdominal pain and jaundice (Medicine (Baltimore) 2018;97:e11015)
- 67 year old woman with chest pain and a lung nodule (Am J Case Rep 2018;19:35)
- 70 year old man with mass forming tumor with portal vein and bile duct thrombus (Int J Surg Case Rep 2017;40:13)
Treatment
- Surgical resection of the tumor is the potential curative therapy
- Resistant to the traditional chemotherapy but recent studies show increased survival rate with EGFR inhibitor erlotinib and gemcitabine / cisplatin combination therapy (Lancet Oncol 2012;13:181)
Gross description
- Usually large, nonencapsulated, well demarcated, firm (due to desmoplastic reaction), white-tan to gray and nodular intrahepatic mass
- More frequent in the right lobe of the liver
- Satellite nodules are present in 30%
- Calcification is common
- Noncirrhotic background liver in most cases
- Grossly classified into 3 types in some articles (World J Hepatol 2010;2:419):
- Mass forming: hepatic parenchymal solid mass
- Periductal infiltrating: infiltrates along the portal tracts, causing bile duct strictures
- Intraductal growth: papillary or polypoid growth inside a dilated bile duct
Gross images
Images hosted on other servers:
Mass forming cholangiocarcinomas
Periductal infiltrating cholangiocarcinoma
Microscopic (histologic) description
- Intrahepatic cholangiocarcinoma consists of infiltrating well formed or cribriform glands in an abundant fibrous stroma
- Malignant glands are lined by cells with varying degrees of atypia and pleomorphism
- Usually well differentiated adenocarcinoma with mild atypia, intracytoplasmic lumina and intraluminal cellular debris; however, focal atypia with marked pleomorphism can also be present
- Commonly infiltrates between hepatic parenchymal cords at the periphery of the tumor
- Multicentricity and perineural invasion are common
- Histologic variants include mucinous, signet ring cell, clear cell, lymphoepithelioma-like, thyroid follicular-like, adenosquamous and sarcomatoid
Microscopic (histologic) images
Contributed by Omid Savari, M.D.
With necrosis
With sclerotic stroma
High magnification
Infiltrating hepatic parenchyma
Poorly differentiated
Images hosted on other servers:
Various images
Cytology description
- Isolated, clusters and sheets of cuboidal or columnar cells with various degrees of nuclear enlargement and pleomorphism
- Wide range of glandular differentiation on cell block
- > 10 proliferating ductules on FNA is helpful to differentiate cholangiocarcinoma from metastatic adenocarcinomas (Diagn Cytopathol 2000;22:359)
Positive stains
Molecular / cytogenetics description
- Mutations in KRAS (22%), BRAF (7%), EGFR (2%), IDH1 / IDH2 (14%), MET, activation of mTOR, overexpression of cyclin D1, overexpression of p21, inactivating mutations of DPC4 (13 - 15%) and TP53 (15%), SMAD4 (Oncogene 2013;32:4861, Surg Oncol Clin N Am 2009;18:215)
- Chromosomal gains of 1q, 5p, 7p, 8q, 17q and 20q and losses of 1p, 4q, 8p, 9p, 17p and 18q (Curr Opin Gastroenterol 2012;28:266)
Differential diagnosis
- Metastatic adenocarcinoma: immunohistochemistry and clinical history are helpful to rule out metastasis
- Hepatocellular carcinoma: positive for hepatocyte markers (HepPar1, arginase, glypican 3), negative for CK7
- Benign ductular reactions: uniform growth pattern with lack of atypia and perineural invasion
- Epithelioid hemangioendothelioma: positive for endothelial markers (CD31, CD34), negative for AE1/3 and CK7
- Bile duct adenoma
Additional references
Board review style question #1
What are the mutations associated with liver fluke associated cholangiocarcinoma?
- BAP1 and IDH1 / 2
- BRAF and MET
- mTOR and MET
- TP53 and SMAD4
Board review style answer #1
D. TP53 and SMAD4 mutations are more frequent in liver fluke associated cholangiocarcinoma.
Board review style question #2
Which of the following regarding intrahepatic cholangiocarcinoma risk factors is false?
- Multiple bile duct hamartomas are not a risk factor
- Cirrhosis is an independent risk factor
- Hepatolithiasis is associated with a 6 to 50 fold increased risk of intrahepatic cholangiocarcinoma
- Non liver fluke associated cholangiocarcinoma is associated with BAP1 and IDH1 / 2 gene mutations
Board review style answer #2
A. Multiple bile duct hamartomas (von Meyenburg complexes) are a risk factor for intrahepatic cholangiocarcinoma.
